The introduction of HIV antiretroviral medication (ARVs) in Africa has resulted in substantial reductions in morbidity and mortality. This project is studying the impact of ARVs on community level incidence in the Rakai Community Cohort Study in Uganda, the impact of ARVs on HIV transmission among HIV discordant couples, impact of immunologic monitoring, and potential delays in detecting virologic failure on transmitted and acquired genotypic antiretroviral resistance. We have shown complete elimination of transmission among discordant couples on ARVs and continue to scale up treatment. We have observed declining incidence among Rakai cohort participants since the introduction of ARVs and safe male circumcision with an even greater decline among men (benefiting from both MMC and exposure to female partners on treatment) supporting the current scale up of combination HIV prevention. One concern with increased use of ARVs in sub-Saharan Africa is the extent by which viral resistance will develop over time among the non-clade B HIV-1-infected individuals. We measured the levels of transmitted antiretroviral drug resistance among 51 recently infected RCCS seroconverters with documented seroconversion between November 2012 and October 2013. We found low rates of transmitted antiretroviral drug resistance with only 2 individuals (4%) having resistance to NNRTIs and no resistance found to NRTIs or PIs. Viral load monitoring (VLM) to identify individuals failing ART is not widely available in resource-limited settings; most programs use clinical or immunological monitoring (IM) only. Routine viral load monitoring during the first 3 years of ART reduced the rate of accumulated genotypic resistance to commonly used ART in Uganda. In collaboration with other adult cohorts in Africa, we showed that delayed switch of antiretroviral therapy after virologic failure is associated with elevated mortality highlighting the importance of timely switching to second line regimens. It is unclear whether ongoing CD4 monitoring is needed following immunologic and virologic response to antiretroviral therapy (ART). We investigated the proportion of clients who achieved a virologic and immunologic response and then had a subsequent CD4 count<200 cells/&#956;l despite continued virologic suppression. Included in this analysis were clients receiving ART through the Rakai Health Sciences Program between June 2004-May 2013 who achieved a CD4&#8805;200 cells/&#956;l and VL&#8804;400 copies/ml and who had 3 sets of CD4 and VL measurements (defined as a sequence) within a 390 day period. Among 1553 clients, only 43 (2.8%) clients developed CD4 declines, the majority, 32/43 (74%), among individuals whose initial CD4 was <300 cells/&#956;l. Of the 43 clients with CD4 declines, 24 had an additional CD4 measurement and 20/24 (83%) achieved a CD4&#8805;200 cell/&#956;l on their next measurement (median 285 cells/ul; IQR 220-365). Clients who achieved an immunologic and virologic response to ART were unlikely to experience a subsequent CD4 count decline to <200 cells/&#956;l, and among those experiencing a decline, the majority were transient in nature. Thus, ongoing CD4 monitoring could be omitted. Herpes simplex virus type 2 (HSV-2) has been shown to up-regulate HIV-1 replication at the cellular level. We investigated the impact of daily suppressive acyclovir on HIV-1 disease progression in Rakai, Uganda. We enrolled 440 HIV-1, HSV-2 dually infected adults with CD4+ T-cell counts 300-400 cells/L and not on antiretroviral therapy in a randomized controlled trial with each arm receiving either acyclovir 400 mg orally twice daily or placebo; participants were followed for 24 months. The primary outcome was CD4 <250 or ART initiation for WHO stage IV disease. In a sub-analysis stratified by baseline VL, participants with baseline HIV VL > 50 000 copies/ml treated with Acyclovir had a 38% reduced rate of disease progression compared to placebo (p=0.03). Suppressive acyclovir may be warranted among HSV-2/HIV-1 dually infected individuals not yet on ARVs, particularly among those with high viral loads. In a secondary analysis, we found that the rate of GUD and HSV-2 shedding doubled in the first 3 months after ARV initiation, returning to baseline by 6 months suggesting a possible IRIS effect. Women who participated in the study were monitored every six months for changes in soluble CD14 (sCD14), a marker for monocyte activation, and CRP, a marker for general immune activation. Initial levels of sCD14 and CRP were not predictive of HIV disease progression when controlling for initial CD4+ cell count and HIV viral load. sCD14 levels, but not CRP, decreased in the Acyclovir treatment arm at a significantly faster rate than the placebo group, which was independent of changes in HIV viral load and CD4+ cell count in a multi-variant mixed-effects model (p=0.039). However, the magnitude of this decrease was relatively small with a total estimated decrease of sCD14 of 2.2% of initial levels. These data suggests that monocyte activation may play a minor role in the ability of daily Acyclovir use to slow HIV disease progression. HIV and malaria exert co-pathogenic effects. Malaria surveillance data is necessary for public health strategies to reduce burden in high HIV prevalence settings. The rural district of Rakai, Uganda, registers an HIV prevalence of 9% (age 15-59 yrs cf. national prevalence of 7.3%). We designed a longitudinal cohort study to measure the burden of malaria in Rakai. We recruited 1,640 participants, including 975 children aged 6 months-10 years, 393 adult caregivers, and 272 adolescent/adult household members from 393 randomly selected households within two representative communities. 1,459 (89%) participants completed all study follow-up. CM was identified at 355 (1.7%) study visits, with highest rates of CM identified in infants <3 years, and rates decreased with age. AP was identified at 3,041 (14.4%) study visits, with rate of 11.2% for <3 years and >20% among 6-17 years age cohorts. P. falciparum was identified in 92%, P. vivax in 6%, and P. malariae in 6% of smears. 994 (61%) individuals had at least positive smear; 342 (34%) had one positive result, 203 (20%) had two, 115 (12%) had three, and 334 (34%) had > 3 positive smears during annual follow-up. Seasonal rates generally followed the rains and peaked during July, then decreased through November before increasing again. Plasmodium falciparum infection remains high among patients in Rakai, Uganda, an area of high HIV prevalence. Optimizing the HIV care cascade is a critical component to achieving an AIDS free generation globally. We continue to examine factors associated with success and challenges in the treatment cascade in Rakai. Preliminary analysis of 1783 HIV infected Rakai Community Cohort Study participants in 2009 revealed that 1160 (66%) were linked to care, 848 (48%) were ART eligible at CD4<350, 631 (35%) were receiving ART and 511 of the total HIV infected (32%) were virologically suppressed. Although these numbers are better than those presented by Gardener et al based on US data, we continue to examine modifiable factors which could improve the treatment cascade success.